Alzheimer's disease (AD) is the most common form of dementia affecting the elderly population today; however, there is currently no accurate description of the etiology of this devastating disorder. No single factor has been demonstrated as being causative; however, an alternative co-factors theory suggests that the interaction of multiple risk factors is responsible for AD. We have used this model, in combination with the original cholinergic hypothesis of AD to propose a “new” cholinergic hypothesis that we present in this review. This new version takes into account recent findings from the literature and our reports of removal of medial septum cholinergic projections to the hippocampus reduces both behavioural and anatomical plasticity, resulting in greater cognitive impairment in response to secondary insults (stress, injury, disease, etc.). We will first summarize the experimental results and discuss some potential mechanisms that could explain our results. We will then present our ‘new’ version of the cholinergic hypothesis and how it relates to the field of AD research today. Finally we will discuss some of the implications for treatment that arise from this model and present directions for future study.